Bhlhe40, also known as basic helix-loop-helix transcription factor 40, is a key transcription factor. It plays significant roles in multiple biological processes, associated with pathways like hypoxia, endoplasmic reticulum stress, mTOR, and TGFβ signaling. It is important in immunity, autoimmunity, and various disease conditions including cancer [1,2,3,5]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In pancreatic cancer, Bhlhe40-driven pro-tumour neutrophils with hyperactivated glycolysis exist in the tumour microenvironment, and Bhlhe40 is a key regulator in neutrophil polarisation towards a pro-tumour phenotype [1]. Bhlhe40 also inhibits ferroptosis in pancreatic cancer cells via upregulating SREBF1 [2]. In metastatic colorectal cancer, it promotes the epithelial-mesenchymal transition (EMT), proliferation, invasion, migration, and liver metastasis of cancer cells [3]. In the context of CD8+ T cell exhaustion, it regulates a key differentiation checkpoint between progenitor and intermediate exhausted T cell subsets [4]. In Mycobacterium tuberculosis infection, deletion of Bhlhe40 in lung macrophages and dendritic cells increases mouse susceptibility, and Bhlhe40 promotes pro-inflammatory responses in myeloid cells via IL-10-dependent and-independent mechanisms [6].

In conclusion, Bhlhe40 is crucial in regulating various biological functions including cell polarisation, metabolic processes, and immune responses. Its dysregulation is associated with pancreatic cancer, metastatic colorectal cancer, and immune-related diseases. The use of KO/CKO mouse models has provided important insights into its role in these disease areas, facilitating a better understanding of disease mechanisms and potentially guiding the development of new therapeutic strategies.